Converging lines of evidence have highlighted the involvement of lipoprotein receptors in common, sporadic cases of Alzheimer's disease (AD). The apolipoprotein E (apoE) e4 allelic variant increases AD risk, and the apoE receptors have been linked to the metabolism of the B-amyloid precursor protein (APP) and beta-amyloid peptide (AB), which are believed to play a central role in AD. Using cDNA microarrays to screen changes in gene expression in AD patients, we discovered altered expression of LR11, a multifunctional apoE receptor that is expressed predominantly in brain. LR11 has not previously been linked to AD, but our exciting preliminary findings reveal marked loss of LR11 among vulnerable neurons in AD. In addition, LR11 appears to interact with APP, and we have found important links between LR11 expression and levels of AB These observations provide a strong foundation for the central hypothesis of this proposal: The multifunctional apoE receptor LR11 participates in Alzheimer's disease pathogenesis through its interactions with B-amyloid precursor protein and AB peptide. In Aim 1, we will characterize the molecular interactions of LR11 with APP and generate modified LR11 constructs that will be used in subsequent Aims. In Aim 2, we will examine the ability of LR11 to influence the subcellular distribution of APP and assess the effects on proteolytic processing of APP. In Aim 3, complementary studies will test the ability of LR11 to modulate AB production and mediate AB clearance. In Aim 4, we will generate and characterize cell culture and mouse model systems with reduced LR11 levels to mimic the loss of expression observed in AD brains. These Aims will test our central hypothesis and the findings will generate insights into the biology of apoE receptors, and the results may identify LR11 as an important new target for AD therapeutics.